EP2099784B1 - 1,5-diphenyl-3-pyridinylamino-1,5-dihydrioyrrolidin-2-one als cb1-rezeptor-modulatoren - Google Patents

1,5-diphenyl-3-pyridinylamino-1,5-dihydrioyrrolidin-2-one als cb1-rezeptor-modulatoren Download PDF

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EP2099784B1
EP2099784B1 EP07871196A EP07871196A EP2099784B1 EP 2099784 B1 EP2099784 B1 EP 2099784B1 EP 07871196 A EP07871196 A EP 07871196A EP 07871196 A EP07871196 A EP 07871196A EP 2099784 B1 EP2099784 B1 EP 2099784B1
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phenyl
trifluoromethyl
add
solution
compound
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EP2099784A2 (de
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John Mehnert Schaus
Perry Clark Heath
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Eli Lilly and Co
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones

Definitions

  • the CB 1 receptor family is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs.
  • the CB 2 receptor is found primarily in the immune system.
  • the pharmacology and therapeutic potential for cannabinoid receptor ligands has been reviewed ( Exp. Opin. Ther. Patents 1998, 8, 301-313 ; Ann. Rep. Med. Chem., A. Doherty, Ed.; Academic Press, NY 1999, Vol. 34, 199-208 ; Exp. Opin. Ther. 2000, 10, 1529-1538 ; Trends in Pharma. Sci. 2000, 21, 218-224 ).
  • CB 1 receptor agonists have been associated with stimulation of feeding, anemetic properties, analgesia, reduction in intraocular pressure in glaucoma, and alleviation of muscle spasms in multiple sclerosis.
  • CB 1 receptor antagonists have been shown effective for reducing feeding and body weight in animal models of obesity.
  • most compounds that modulate CB1 receptor activity have the pharmacological property of inverse agonism which reduces basal CB1 receptor signal transduction as well as the activity of blocking CB1 agonist dependent receptor stimulation.
  • CB 1 receptor compounds A number of selective, centrally acting CB 1 receptor compounds are currently in development for the treatment of obesity. Nevertheless, there still remains a need for CB 1 receptor compounds which have increased in vivo potency which are low molecular weight, and have pharmacokinetic and pharmacodynamic properties that provide therapeutic benefit while minimizing adverse events. See for example WO 2007/020502 .
  • CB 1 inverse agonists have been shown to further potentiate the activity of antipsychotic agents in assays.
  • current antipsychotic therapies are more or less effective at controlling positive symptoms, such therapies are not as effective in treating the negative and cognitive symptoms, rendering many patients incapable of leading normal lives.
  • Convergent evidence suggests drugs that enhance neuronal activation in specific brain areas, hippocampal, striatal, and cortical areas in particular, would be effective in treating both negative and cognitive symptoms.
  • the weight loss effects of CB 1 receptor compounds have been demonstrated in animal models of antipsychotic treatment-induced weight gain and therefore may also be effective in controlling the treatment-emergent weight gain and metabolic syndrome seen with current antipsychotic therapies.
  • CB 1 receptor compounds have been shown to reduce alcohol consumption in animal models of alcohol drinking and therefore may be useful in the treatment of substance abuse.
  • CB 1 receptor compounds While oral administration is a preferred route of drug delivery, many CB 1 receptor compounds suffer from poor oral bioavailability as a consequence of their limited solubility in aqueous media and their metabolic lability. Because of the high lipophilicity of the endogenous cannabinoid ligands and the complementary site to which they bind in the CB 1 receptor, known CB 1 receptor compounds are also highly lipophilic. This high lipophilicity leads to poor solubility in aqueous media which limits oral absorption and bioavailability. See for example WO 2007/020502 .
  • the present invention provides a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to Formula (Ia) and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the present invention provides the pharmaceutical composition, wherein the compound of Formula (Ia) is present in optical purity greater than 90%ee.
  • the pharmaceutical composition wherein the compound of Formula (Ia) is present in optical purity greater than 95%ee.
  • An embodiment of the present invention provides a compound according to Formula (Ia) for use in therapy.
  • the present invention provides a compound according to Formula (Ia) for use in the treatment of a disorder selected from: an eating disorder associated with excessive food intake, obesity and schizophrenia. Also disclosed herein is a compound according to Formula (Ia) for use in the treatment of a disorder selected from cognitive impairment associated with schizophrenia, substance abuse or alcohol dependence, smoking cessation and treatment emergent weight gain observed during treatment with an atypical antipsychotic.
  • the present invention provides the use of a compound according to Formula (Ia) in the manufacture of a medicament for the treatment of a disorder selected from: an eating disorder associated with excessive food intake, obesity and schizophrenia. Also disclosed herein is the use of a compound according to Formula (1a) in the manufacture of a medicament for the treatment of a disorder selected from cognitive impairment associated with schizophrenia, substance abuse or alcohol dependence, smoking cessation and treatment emergent weight gain observed during treatment with an atypical antipsychotic.
  • An embodiment of the invention provides a compound according to Formula (Ia), or a pharmaceutically acceptable salt thereof, for use in treating a condition in a mammal which is treatable by blockade of CB 1 receptors via an inverse agonism mechanism.
  • An embodiment of the invention provides a compound according to Formula (Ia), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with an antipsychotic agent in treating a condition in a mammal.
  • the condition is an eating disorder associated with excessive food intake.
  • the condition is obesity.
  • the condition is schizophrenia.
  • the condition is cognitive impairment associated with schizophrenia.
  • the condition is substance abuse or alcohol dependence.
  • the condition is smoking cessation.
  • condition is treatment emergent weight gain observed during smoking cessation.
  • An embodiment of the invention provides a compound according to Formula (Ia) for use in simultaneous, separate or sequential combination with an antipsychotic agent in the treatment of a disorder selected from: weight gain, obesity and schizophrenia. Also disclosed herein is a compound according to Formula (1a) for use in simultaneous, separate or sequential combination with an antipsychotic agent in the treatment of a disorder selected from: cognitive impairment associated with schizophrenia, substance abuse or alcohol dependence, smoking cessation and treatment emergent weight gain observed during treatment with an atypical antipsychotic.
  • the invention provides the use of a compound according to Formula (I) in the manufacture of a medicament for use in combination therapy for the treatment of a disorder selected from: weight gain, obesity and schizophrenia, wherein said medicament is to be administered in simultaneous, separate or sequential combination with an antipsychotic agent.
  • a compound according to Formula (I) in the manufacture of a medicament for use in combination therapy for the treatment of a disorder selected from: cognitive impairment associated with schizophrenia, substance abuse or alcohol dependence, smoking cessation and treatment emergent weight gain observed during treatment with an atypical antipsychotic, wherein said medicament is to be administered in simultaneous, separate or sequential combination with an antipsychotic agent.
  • the present invention provides a compound according to Formula (Ia), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with an antipsychotic agent in treating a condition in a mammal which is treatable by blockade of CB 1 receptors via an inverse agonism mechanism.
  • the present invention provides a compound according to Formula (Ia), or a pharmaceutically acceptable salt thereof, for use in treating a condition in a mammal.
  • the condition is schizophrenia.
  • the condition is weight gain.
  • the condition is obesity.
  • the condition is cognitive impairment associated with schizophrenia.
  • the condition is substance abuse or alcohol dependence.
  • the condition is smoking cessation.
  • condition is treatment emergent weight gain observed during treatment with an atypical antipsychotic.
  • a preferred aspect of this invention provides compounds of Formula (Ia) that are substantially pure enantiomers.
  • each of the following specific classes of compounds of Formula (Ia) are contemplated as aspects of the present invention:
  • enantiomerically pure compounds may be prepared by purification of the desired enantiomer of a compound of Formula (I) from a mixture of enantiomers of this compound.
  • the desired enantiomer of a compound of Formula (I) may also be prepared by synthesis according to the following general schemes by using precursors that are substantially enantiomerically pure. Those skilled in the art will recognize that either resolution of final compounds or of intermediates will provide compounds of Formula (I) in substantially enantiomerically pure form, to yield for example, compounds of Formula (Ia), and will employ the method which is most convenient.
  • a substantially pure diastereomer may be isolated from a mixture of diastereomers using methods known in the art.
  • Methods for purification of diastereomers include chromatography and crystallization.
  • a mixture of enantiomers may be separated into the individual substantially pure enantiomers by the process known as resolution.
  • Enantiomers may be resolved through the use of chromatography using a chiral stationary phase. Suitable chiral solid phases include polysaccharide-based stationary phases such as Chiralpak AD and Chiracel OJ (sold by Chiral Technologies, Inc.).
  • enantiomers of basic compounds may be resolved by conversion to a mixture of diastereomeric salts by treatment with a chiral acid.
  • the desired diastereomeric salt is isolated by, for example, crystallization.
  • the substantially enantiomerically pure basic compound may be isolated by treatment with base.
  • Examples of chiral acids include (-)-tartaric acid, (+)-tartaric acid, (-)-mandelic acid, (+)-mandelic acid, (-)-ditoluoyltartaric acid and (+)-ditoluoyltartaric acid.
  • Enantiomers of acidic compounds may be resolved in an analogous manner using a substantially enantiomerically pure base. Examples of such bases include R-alpha-methylbenzylamine, S-alpha-methylbenzylamine, and brucine.
  • Another method for the resolution of a racemic mixture involves reaction with a substantially enantiomerically pure chiral reagent (referred to here as a chiral auxiliary) to form a covalent bond.
  • a substantially enantiomerically pure chiral reagent referred to here as a chiral auxiliary
  • This reaction results in a mixture of diastereomers, which is purified according to methods known in the art. All, or a portion, of the chiral auxiliary may then be cleaved from the molecule to generate a compound which is substantially enantiomerically pure. In some cases, the asymmetric center introduced by the chiral auxiliary may be retained in the final product.
  • references to the compounds of Formulas (I) or (Ia) are meant to also include the pharmaceutically acceptable salts thereof.
  • compounds of Formulas (I) or (Ia) are selective for the CB 1 receptor in preference to the CB 2 receptor.
  • these CB 1 receptor ligands act as antagonists of CB 1 receptor function and have inverse agonist properties as well.
  • compounds of Formula (Ia) are modulators of the CB 1 receptor, and as such are useful for prevention and treatment of conditions associated with the CB 1 receptor.
  • Such conditions include, for example, memory deficits, cognitive disorders, negative symptoms of schizophrenia, substance abuse disorders (particularly to opiates, alcohol, and nicotine), obesity, metabolic disorders and eating disorders associated with excessive food intake. See DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders. Revised, 4th Ed., Text Revision (2000 ).
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders 4th Ed., (1994 ).
  • the DSM-IV and DSM-IV-TR were prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric Association, and provides descriptions of diagnostic categories.
  • the skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for pathologic psychological conditions and that these systems evolve with medical scientific progress.
  • the compounds of Formula (Ia) can also be used to ameliorate weight gain, whether or not the associated weight gain subject can be classified as clinically obese.
  • An effective amount of the compounds of Formula (Ia), may be administered to a patient in need of such treatment or prophylaxis.
  • the need for a prophylactic administration according to the present invention is determined via the use of well-known risk factors.
  • the effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration, other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
  • the prophylactic or therapeutic dosage of a compound of Formula (Ia) will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula (Ia) and its route of administration.
  • the dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration and/or the characteristics of the dosage form (i.e., modified release), the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage may be correspondingly larger for the less frequent administration. When administered via, transdermal routes, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the salt of the claimed compounds must be pharmaceutically acceptable.
  • the salt of the claimed compounds must be pharmaceutically acceptable.
  • LC column Zorbax Eclipse XDB C8 4.6 X 150 mm 5 uM; Gradient: 20-90% acetonitrile w/0.01% trifluoracetic acid in 13.0 minutes.
  • Example 2 4-methylbenzenesulfonate
  • the GTP-binding assay buffer (20 mM Hepes, 100 mM NaCl, 5 mM MgCl 2 , pH 7.4), the CHO or Sf9 cell membranes expressing CB 1 or CB 2 , (Applied Cell Sciences, Gaithersburg, MD; PerkinElmer Life Sciences, Boston, MA; prepare membranes as previously described (DeLapp et al., 1999)), Example 2 and the 500 pM GTP- ⁇ - 35 S (PerkinElmer Life Sciences, Boston, MA). Perform antagonist dose reponses in the presence of a saturating dose of a full agonist (methanandamide).
  • SEM standard error of the mean
  • Example 2 exhibits potent human and rat CB 1 antagonism with no measurable antagonism of the human CB 2 receptor.
  • the data indicates Example 2 is a potent CB 1 antagonist/inverse agonist at both rat and human receptors with no antagonism of human CB 2 receptors.
  • Example 2 summarizes the agonist properties of Example 2 in Sf9 cell membranes from cells expressing human CB 1 or CB 2 receptors. These data demonstrate that Example 2 is an inverse agonist at the human CB 1 receptor as evidenced by agonist efficacy (Table 2) less than zero which indicates that the compound decreased basal constitutive activity of the CB 1 receptor in vitro. Example 2 does not have any measurable CB 2 agonist activity (Table 2).
  • mice Receive NIH male Swiss mice (Harlan Sprague-Dawley, weight 20-25g) 7 to 10 days prior to testing. House 12 mice per cage. Test only animals that weigh 25-30g. On the day of testing, bring animals to the testing room at least 1 hour prior to dosing. When dosing starts, dose at 6-8 minute intervals between each dose with each mouse receiving either Administer vehicle (1% CMC, 0.5% SLS, 0.08% povidone, 0.05% antifoam) or Example 2, p.o. Next, place mice in a clean cage (4 mice per cage). After 90 minutes, start the test following a 90 minute pre-treatment with Example 2 or vehicle.
  • Administer vehicle 1% CMC, 0.5% SLS, 0.08% povidone, 0.05% antifoam
  • MED minimum effective dose
  • Cortical Activation cFos Activation.
  • Example 2 Characterize Example 2 for its ability to activate gene expression and neurochemical efflux in cortical and subcortical regions and to interact with the prototypical atypical antipsychotic agent clozapine.
  • PFC prefrontal cortex
  • NAc nucleus accumbens
  • DL-Str dorsolateral striatum
  • Clozapine and Example 2 both individually tend to or significantly enhance cortical and subcortical Fos reactivity. Observe Example 2 enhancing the effects of clozapine alone at both 1 and 10 mg/kg, p.o.
  • Example 2 Increases cFos expression in rat brain in both prefrontal cortex and subcortical regions by Example 2.
  • Addition of Example 2 to clozapine results in augmentation of cFos expression induced by clozapine in brain areas critical to cognitive function and negative symptom control.
  • Results Increase rat cortical monoamine and metabolite levels by Example 2 doses as low as I mg/kg, p.o.
  • Example 2 Evaluate Example 2 for its ability to reduce consumption of ethanol in rats selectively bred for high oral ethanol intake (P rats). In addition, study the effects of Example 2 under conditions in which effects of the compound on motivation or the control of behavior by ethanol could be assessed.
  • Example 2 Study the effects of Example 2 on female, alcohol-preferring (P) rats on alcohol consumption under a continuous free access paradigm.
  • test the standard opioid antagonist naltrexone. Monitor voluntary consumption of 15% (v/v) ethanol.
  • Suspend Example 2 in vehicle 1% CMC, 0.5% SLS, 0.08% povidone, 0.05% Dow Coming antifoam 1510 US) and give p.o.3 hours prior to the onset of the dark cycle.
  • measure locomotor activity via infrared sensor.
  • Results Consumption of ethanol but not water was decreased in a dose-dependent manner by orally-administered Example 2. Naltrexone, at higher doses, was also able to reduce ethanol intake.
  • Example 2 did not significantly alter locomotor activity of these rats until a dose of 10 mg/kg.
  • Example 2 Assess the ability of Example 2 to reduce the motivational drive controlling ethanol intake.
  • Results Decrease cumulative food intake by administrating Example 2 once daily orally throughout the 14-day study. Consistent with reduced food intake, observe reduction of cumulative body weight following the 14-day oral treatment with Example 2, producing an estimated T17 of 0.13 mg/kg. Measure body composition analysis by quantitative nuclear magnetic resonance (QNMR) showing significant reductions in fat mass at doses ranging from 0.1 - 10 mg/kg with minimal changes in fat free mass at one of the highest doses.
  • QNMR quantitative nuclear magnetic resonance
  • Example 2 Produce a significant reduction in body weight from vehicle treated controls by daily oral administration of Example 2 for 14 days to diet-induced obese (DIO), male Long-Evans rats maintained on a high-energy diet reduced food intake.
  • T 17 efficacy dose of 0.13 mg/kg/day for Example 2 for producing a change in body mass from control. Analyze changes in body composition to determine that the reduced body mass results from a significant reduction in fat mass at doses up to 10 mg/kg (the highest dose tested).

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Claims (7)

  1. Verbindung der Formel
    Figure imgb0024
     oder ein pharmazeutisch akzeptables Salz hiervon.
  2. Pharmazeutische Zusammensetzung, die eine Verbindung nach Anspruch 1 und einen pharmazeutisch akzeptablen Träger, ein pharmazeutisch akzeptables Verdünnungsmittel oder einen pharmazeutisch akzeptablen Hilfsstoff umfasst.
  3. Pharmazeutische Zusammensetzung nach Anspruch 2, wobei die Verbindung in einer optischen Reinheit von größer als 90 % ee vorliegt.
  4. Pharmazeutische Zusammensetzung nach Anspruch 2, wobei die Verbindung in einer optischen Reinheit von größer als 95 % ee vorliegt.
  5. Verbindung nach Anspruch 1 zur Verwendung bei einer Therapie.
  6. Verbindung nach Anspruch 1 zur Verwendung bei der Behandlung einer Essstörung in Verbindung mit übermäßiger Nahrungsaufnahme, Fettleibigkeit oder Schizophrenie.
  7. Verbindung nach Anspruch 1 zur Verwendung in einer gleichzeitigen, getrennten oder sequenziellen Kombination mit einem antipsychotischen Mittel bei der Behandlung von Fettleibigkeit oder Schizophrenie.
EP07871196A 2006-10-23 2007-10-22 1,5-diphenyl-3-pyridinylamino-1,5-dihydrioyrrolidin-2-one als cb1-rezeptor-modulatoren Not-in-force EP2099784B1 (de)

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PL07871196T PL2099784T3 (pl) 2006-10-23 2007-10-22 1,5-difenylo-3-pirydynyloamino-1,5-dihydrioirrolidyn-2-ony jako modulatory receptora cb1
SI200731118T SI2099784T1 (sl) 2006-10-23 2007-10-22 1,5-difenil-3-piridinilamino-1,5-dihidrorirolidin-2-oni kot modulatorji receptorja cb1
CY20131100071T CY1113563T1 (el) 2006-10-23 2013-01-25 1,5-διφαινυλ-3-πυριδινυλαμινο-1,5-διυδριουρρολιδιν-2-ονες ως ρυθμιστες υποδοχεα cb1

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US86254006P 2006-10-23 2006-10-23
PCT/US2007/082041 WO2008070305A2 (en) 2006-10-23 2007-10-22 1, 5-diphenyl-3-pyridinylamino-1, 5-dihydropyrrolidin-2-one as cbl' receptor modulator

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EP07871196A Not-in-force EP2099784B1 (de) 2006-10-23 2007-10-22 1,5-diphenyl-3-pyridinylamino-1,5-dihydrioyrrolidin-2-one als cb1-rezeptor-modulatoren

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AR063497A1 (es) * 2006-10-23 2009-01-28 Lilly Co Eli Compuesto de pirrodinil -2-ona, intermediario para la sintesis del mismo, composicion farmaceutica que lo comprende y su uso para preparar un medicamento
MX2010011547A (es) * 2008-04-22 2010-11-09 Lilly Co Eli Compuestos de 1,5-difenil-pirrolidin-2-ona como ligandos de cb-1.
KR101276955B1 (ko) * 2008-04-22 2013-06-20 일라이 릴리 앤드 캄파니 Ｃｂ-１ 리간드로서 １,５-디페닐-피롤리딘-２-온 화합물
WO2010057000A2 (en) * 2008-11-13 2010-05-20 The Trustees Of Columbia University In The City Of New York Neuraminidase inhibitors and uses thereof
ITTO20110641A1 (it) * 2010-07-15 2012-01-16 Oleg Iliich Epshtein Composizioni farmaceutiche e metodi di trattamento
CA2891122C (en) 2012-11-14 2021-07-20 The Johns Hopkins University Methods and compositions for treating schizophrenia
US20240158384A1 (en) * 2020-12-14 2024-05-16 The Board Of Trustees Of The Leland Stanford Junior University Cb2 receptor agonists
WO2023205180A1 (en) 2022-04-19 2023-10-26 Nurix Therapeutics, Inc. Biomarkers for cbl, and compositions and methods for their use
US20230414598A1 (en) 2022-06-22 2023-12-28 Nurix Therapeutics, Inc. Combination therapies with cbl-b inhibitor compounds and antiemetic agents

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US20060035245A1 (en) * 2004-04-20 2006-02-16 Ason Brandon L Modulators of enzymatic nucleic acid elements mobilization
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CA2667372A1 (en) 2008-06-12
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EP2099784A2 (de) 2009-09-16
KR101088229B1 (ko) 2011-11-30
PT2094684E (pt) 2011-01-28
CA2667210C (en) 2013-09-24
WO2008070305A3 (en) 2008-08-28
CL2007003002A1 (es) 2008-06-06
KR20090071613A (ko) 2009-07-01
DK2099784T3 (da) 2013-01-14
SI2094684T1 (sl) 2011-04-29
PE20080926A1 (es) 2008-07-19
US7998985B2 (en) 2011-08-16
CN101528733A (zh) 2009-09-09
AU2007329808A1 (en) 2008-06-12
MX2009004054A (es) 2009-04-27
EA200970404A1 (ru) 2009-10-30
ES2398388T3 (es) 2013-03-15
JP2010507590A (ja) 2010-03-11
JP5331002B2 (ja) 2013-10-30
EP2094684A2 (de) 2009-09-02
EP2094684B1 (de) 2010-12-22
WO2008070306A2 (en) 2008-06-12
WO2008070306A3 (en) 2008-07-31
US20090275618A1 (en) 2009-11-05
US8168659B2 (en) 2012-05-01
SI2099784T1 (sl) 2013-02-28
WO2008070305A2 (en) 2008-06-12
PT2099784E (pt) 2013-01-04
TW200825067A (en) 2008-06-16
KR101088236B1 (ko) 2011-11-30
EA200970405A1 (ru) 2009-12-30
ES2356025T3 (es) 2011-04-04
EA015745B1 (ru) 2011-10-31
CN101528732A (zh) 2009-09-09
CN101528732B (zh) 2013-04-03
KR20090069316A (ko) 2009-06-30
PL2094684T3 (pl) 2011-05-31
CA2667372C (en) 2013-09-03
DE602007011495D1 (de) 2011-02-03
EA015175B1 (ru) 2011-06-30
BRPI0717347A2 (pt) 2014-01-14
JP2010507589A (ja) 2010-03-11
US20100016375A1 (en) 2010-01-21
DK2094684T3 (da) 2011-03-14
AR063497A1 (es) 2009-01-28
ATE492543T1 (de) 2011-01-15
CA2667210A1 (en) 2008-06-12
CY1111140T1 (el) 2015-06-11
PL2099784T3 (pl) 2013-05-31
JP5331001B2 (ja) 2013-10-30
AU2007329807A1 (en) 2008-06-12
CN101528733B (zh) 2013-10-16

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